Dysregulated PI3K Signaling in B Cells of CVID Patients

Area of Science:

• Immunology
• Molecular Biology
• Genetics

Background:

• Dysregulated adaptive immunity, including immunodeficiency and autoimmunity, is linked to altered T and B cell signaling pathways.
• Primary immunodeficiencies offer insights into complex immune system regulation.
• Previous studies noted disturbed B-cell receptor (BCR) signaling in common variable immunodeficiency (CVID) patients with T-bet^highCD21^low B cells.

Purpose of the Study:

• To investigate phosphoinositide 3-kinase (PI3K) signaling and its downstream targets in regulating B cell survival, proliferation, and metabolism.
• To differentiate PI3K signaling defects in CVID from those in activated PI3K delta syndrome (APDS).

Main Methods:

• Intracellular flow cytometry
• Imaging flow cytometry
• RNA sequencing (RNAseq)

Main Results:

• CVID patients, particularly those with T-bet^highCD21^low B cells, exhibit increased basal but disturbed BCR-induced PI3K signaling.
• Impaired activation of downstream molecules affects proliferation, survival, and metabolic profiles in CVID B cells.
• Unlike CVID, APDS patients with PI3K gain-of-function mutations do not show impaired BCR-induced AKT-mTOR-S6 phosphorylation, indicating fundamentally different signaling defects.

Conclusions:

• Signaling defects in B cells of CVID and APDS patients are distinct.
• Assessing BCR stimulation response is a valuable diagnostic test for APDS.
• Active PI3K signaling in CVID may sensitize autoreactive T-bet^highCD21^low B cells to mTOR or PI3K inhibition.